CDK4/CDK6 Inhibitors Effective in Older Women, but Have More Side Effects

Older patients with hormone receptor–positive, HER2-­negative, metastatic breast cancer derive similar benefit as younger patients who received cyclin-dependent kinase (CDK)4/CDK6 inhibitors as part of their initial endocrine therapy, according to a pooled analysis of clinical trials presented at the 2017 San Antonio Breast Cancer Symposium.

Across pooled trials, the rates of selected adverse events were similar, but women aged ≥65 years had increased rates of more severe adverse events and dose modifications and interruptions.

“Accrual of older women to clinical trials is challenging. Women over age 75 make up about 4% of the clinical trial population and are underrepresented. Over 40% of breast cancer–related deaths are in women age 70 and older. We have limited data on the safety and efficacy of CDK4/6 inhibitors in older adults,” said lead investigator Harpreet Singh, MD, Scientific Liaison, Cancer in Older Adults, FDA’s Office of Hematology and Oncology Products, who presented the study results.

This retrospective study included clinical trials of CDK4/CDK6 inhibitors used in combination with an aromatase inhibitor as initial endocrine-based therapy for advanced or metastatic breast cancer. The efficacy was assessed based on 1992 patients, and progression-free survival (PFS) was evaluated in 329 patients aged 70 years in the treatment and control groups.

Among patients aged ≥70 years who received a CDK4/CDK6 inhibitor plus an aromatase inhibitor, the median PFS was not reached. In patients aged <70 years, the median PFS was 23.5 months.

“There seems to be a similar benefit no matter what the age of patients,” Dr Singh stated. “No treatment differences were observed across age subgroups.”

The safety and tolerability were assessed in all patients who received at least 1 dose of a CDK4/6 inhibitor; 25% were aged ≥70 years.

Serious adverse events increased with age. Grades 3 and 4 adverse events were reported in 66% of patients aged <65 years versus 80% in those aged ≥65 years and 85% for patients aged ≥70 years. Adverse events leading to treatment discontinuation were reported in 8%, 16%, and 17% of the patients, respectively. Serious adverse events were reported in 16%, 31%, and 33% of the patients, respectively.

The rates of neutropenia and hepatotoxicity were similar across age-groups, but infection, fatigue, and diarrhea trended slightly higher in older patients.

“The eligibility criteria for clinical trials need to be revised and should be based partly on patient-reported outcomes and real-world data,” Dr Singh said.

“Age is one factor we consider when selecting patients for CDK4/6 inhibitor therapy. The patients we tend to treat with these agents in addition to endocrine therapy are those with higher disease burden who are more fit and younger. These data provide some reassurance about the efficacy of CDK4/6 inhibitors in the older population and reinforce our concerns, namely more side effects. The patients in this analysis are not reflective of those we see in clinical practice. We need to assess safety in older patients who are less fit,” said Joseph A. Sparano, MD, Associate Chairman for Clinical Research, Department of Oncology, Montefiore Medical Center, Bronx, NY.

“A single endocrine agent may be sufficient for an 85-year-old with a few comorbidities,” said Rowan Chlebowski, MD, PhD, Research Professor, Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA.

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